Increase of Plasma Biomarkers in Friedreich's Ataxia: Potential Insights into Disease Pathology

Abstract

Background: Therapeutic interventions in Friedreich's ataxia (FRDA) are progressing into clinical trials, and the need for robust and easily accessible biomarkers has arisen.

Objective: This study aimed to consolidate preliminary findings of changes in the levels of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), Tau, and ubiquitin C-terminal hydrolase L1(UCH-L1) in FRDA comparing two large independent cohorts of patients with healthy controls.

Methods: Plasma samples of patients from two large natural history studies (n = 187) and a similar sized cohort of healthy control subjects (n = 127) were assessed using single-molecule array measurements. Age-adjusted biomarker levels were related to patients' genetic profile, clinical progression, and comorbidities, and compared with controls. Sensitivity and specificity were assessed using receiver operating characteristic analyses.

Results: NfL levels were significantly elevated in patients with FRDA younger than 40 years, showing a distinct age-dependent trajectory: levels declined with age in FRDA but increased in controls. Longitudinal data indicated annual NfL reductions between 8% (children) and 13% (young adults < 35 years). This result is discussed in the context of other neurodegenerative conditions, with FRDA being a rare case where NfL levels decrease over time before the age of 40 years. In contrast, tau was consistently elevated across all age groups in FRDA.

Conclusions: NfL is a sensitive biomarker in early FRDA but decreases with age, converging with control values after 35-40 years. This age-dependent pattern must be considered when interpreting the effect of interventions in clinical trials. Especially in younger (age < 10 years) or presymptomatic patients and control subjects, additional longitudinal sampling is warranted. Elevated tau levels suggest involvement in underlying disease pathophysiology. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Friedreich's ataxia; ataxia; biomarkers; neurofilament light.

FIG. 1

Biomarker levels in participants with Friedreich's ataxia (FRDA) (red) and control subjects (blue) by age. Mean lines for samples within 5‐year age bins are depicted in connected dots with 95% confidence intervals (CIs); individual measures are shown as circles: (A) neurofilament light [NfL], (B) glial fibrillary acidic protein [GFAP], (C) t‐tau, and (D) ubiquitin C‐terminal hydrolase L1 (UCH‐L1). [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Changes in neurofilament light (NfL) levels respective to age, color coded by number of GAA1 repeat length. The y‐axis was limited to ±30 pg/mL (one sample changed by −150 pg/mL at age 69 years). [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

Receiver operating characteristic (ROC) curves for neurofilament light (NfL) (A), glial fibrillary acidic protein (GFAP) (B), t‐tau (C), and ubiquitin C‐terminal hydrolase L1 [UCH‐L1] (D); different age cutoffs are depicted by color, with resulting area under the curve (AUC) (%) results. CI, confidence interval. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 4

Neurofilament light (NfL) levels in control subjects (gray) and patients with Friedreich's ataxia (FRDA) relative to age (left) and disease duration (right). Patients with FRDA were grouped and colored by GAA1 repeat length. Solid lines depict polynomial model functions of NfL levels, by respective GAA1‐repeat length group. Control levels were modeled using a linear function over age. [Color figure can be viewed at wileyonlinelibrary.com]